chr2-73385958-A-AGCGGCG

Variant names:

• chr2-73385958-A-AGCGGCG
• rs746896173
• NM_001378454.1:c.100_105dupGCGGCG

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_001378454.1(ALMS1):​c.100_105dupGCGGCG​(p.Ala34_Ala35dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,398,938 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. N36N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: 0.260
• Publications: 1 publications found

Genes affected

ALMS1 (HGNC:428): (ALMS1 centrosome and basal body associated protein) This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014]

ALMS1 Gene-Disease associations (from GenCC):

• Alstrom syndrome

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001378454.1.
• BP6: Variant 2-73385958-A-AGCGGCG is Benign according to our data. Variant chr2-73385958-A-AGCGGCG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000278 (42/150814) while in subpopulation AMR AF = 0.00237 (36/15164). AF 95% confidence interval is 0.00176. There are 2 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378454.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.100_105dupGCGGCG	p.Ala34_Ala35dup	conservative_inframe_insertion	Exon 1 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.100_105dupGCGGCG	p.Ala34_Ala35dup	conservative_inframe_insertion	Exon 1 of 23	NP_055935.4	Q8TCU4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.100_105dupGCGGCG	p.Ala34_Ala35dup	conservative_inframe_insertion	Exon 1 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.100_105dupGCGGCG	p.Ala34_Ala35dup	conservative_inframe_insertion	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000614410.4	TSL:5	c.100_105dupGCGGCG	p.Ala34_Ala35dup	conservative_inframe_insertion	Exon 1 of 16	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes AF: 0.000278 AC: 42 AN: 150814 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00237

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000592

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000510 AC: 71 AN: 139126 AF XY: 0.000407

Gnomad AFR exome AF: 0.000144

Gnomad AMR exome AF: 0.00242

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00349

GnomAD4 exome AF: 0.0000785 AC: 98 AN: 1248124 Hom.: 0 Cov.: 19 AF XY: 0.0000723 AC XY: 45 AN XY: 622358

African (AFR) AF: 0.0000695 AC: 2 AN: 28768

American (AMR) AF: 0.00208 AC: 73 AN: 35040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23832

East Asian (EAS) AF: 0.00 AC: 0 AN: 34376

South Asian (SAS) AF: 0.00 AC: 0 AN: 74610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5244

European-Non Finnish (NFE) AF: 0.0000169 AC: 16 AN: 944766

Other (OTH) AF: 0.000132 AC: 7 AN: 52890

GnomAD4 genome AF: 0.000278 AC: 42 AN: 150814 Hom.: 2 Cov.: 32 AF XY: 0.000353 AC XY: 26 AN XY: 73570

African (AFR) AF: 0.0000486 AC: 2 AN: 41178

American (AMR) AF: 0.00237 AC: 36 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 4972

South Asian (SAS) AF: 0.00 AC: 0 AN: 4748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000592 AC: 4 AN: 67568

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.0000960 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	1	Alstrom syndrome (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.26
Mutation Taster		=84/16	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746896173; hg19: chr2-73613086;